Abstract. The OSU NIH-funded P41 Resource ?Native Mass Spectrometry Guided Structural Biology? proposes to develop native mass spectrometry (nMS) -based tools for the characterization of protease-resistant protein aggregates/oligomers associated with Alzheimer?s disease and its related dementias (AD/ADRD). The Resource students, postdocs, faculty, and staff have no prior Alzheimer?s disease expertise or funding so this supplemental funding would engage multiple new investigators in AD research, carry the expertise forward as students and postdocs move on to other locations, disseminate the results, and provide a community resource to AD investigators, and their MS core facilities at their local units. The nMS-based tools that currently exist in the P41 and tools under development will be used to tackle the AD problem (nMS coupled to ion mobility and multiple activation methods (surface-induced dissociation, collision-induced dissociation, electron capture dissociation) and covalent labeling methods if needed). In order to study AD related aggregates and oligomers, this supplement proposes purchase of a production model Waters Select Series Cyclic IMS instrument, which will be modified by the Resource to include surface-induced dissociation. The proposed instrument is more sensitive and has higher m/z and ion mobility (IM) resolution than the 8-year-old Waters Synapt Series instruments currently in the Resource. The one-year supplement term will focus on method development on the Cyclic IMS for samples from the Nowick lab at UC Irvine (amyloid beta oligomers and amyloid oligomer mimics) and the Kuret lab at OSU (tau). Additional samples, including brain tissue and antibodies and other probes under development, will be provided by Nowick, Kuret, and collaborators of Kuret who are planning to jointly apply for U24 funding. The Resource will work with investigators to illustrate the complementarity of native MS with other structural biology tools, based on experience developed in ongoing non-AD Driving Biomedical Projects and Collaboration & Service projects. At the end of this development, additional AD investigators will be encouraged to propose to work with the P41 under its Collaborate and Service, Training, and Dissemination missions, to work with one of the external core facilities that have been trained in nMS approaches for AD investigations, or, eventually, to work with the OSU U24 Resource network, if funded. Specific Aims are to develop nMS/IM/MS tools for i) in vitro tau and A? oligomers and A? oligomer mimics, ii) in vitro chemical or molecular probes binding to -oligomers, and iii) aggregates/oligomers and probe-bound oligomers from brain tissue. Developing robust and reliable methods for understanding how both A? and tau aggregate in vitro is essential to better understand the molecular mechanism of AD, and consequently for developing effective diagnostic tools and therapies. Characterization of probe/oligomer interactions and assessing their robustness will establish the utility of these probes for basic science, therapeutic or diagnostic applications.